反应详情

温度

-78 °C

Wash potassium hydride (approximately 2 scoops, 35 weight % in mineral oil) with hexanes and decant to remove oil, add tetrahydrofuran (60 mL) and cool to −78° C. Dry a solution of 2,4,6-tris(1-methylethyl)-benzenesulfonyl azide (37.6 g, 121.6 mmol) in tetrahydrofuran (60 mL) over sodium sulfate for 45 minutes. Decant azide solution into the potassium hydride suspension over 15 minutes. Remove cold bath and allow it to warm to ambient temperature for 45 minutes; set aside dry solution. Cool a solution of diisopropylamine (17.0 mL, 121.0 mmol) and tetrahydrofuran (50 mL) to −78° C., add n-butyl lithium (52.1 mL, 130.3 mmol) dropwise over 5 minutes. Remove cold bath and allow it to warm for 15 minutes then cool back to −78° C. Cannulate into a −78° C. solution of 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (34.3 g, 93.1 mmol) in tetrahydrofuran (400 mL) over 5-10 minutes. Stir for one hour at −78° C. then remove cold bath and allow it to warm for 15 minutes (to approximately −45° C.). Cool to −78° C. and add the dried 2,4,6-tris(1-methylethyl)-benzenesulfonyl azide solution via cannula over 5-10 minutes. Remove bath and allow to warm to −5 to 0° C. over 1 hour. Cool in ice/water bath and add acetic acid (26.7 mL, 465.3 mmol) dropwise over 13 minutes. Allow to warm to ambient temperature over 65 minutes and quench with saturated sodium bicarbonate solution (14 Dilute reaction with ethyl acetate (600 mL) and water (2 L), separate layers, back extract from aqueous with ethyl acetate (2×400 mL). Wash combined organics with saturated aqueous sodium bicarbonate solution (500 mL) and brine (500 mL), dry over sodium sulfate and concentrate. Purify the residue by flash chromatography, eluting with ethyl acetate:hexane (0:100 to 100:0) to give the title compound as an oil (39.8 g, 92.3 mmol, 99%). MS (m/z): 410 (M+1).

1. washWash potassium hydride (approximately 2 scoops, 35 weight % in mineral oil) with hexanes
2. customdecant
3. customto remove oil
4. additionadd tetrahydrofuran (60 mL)
5. customRemove cold bath
6. temperatureto warm to ambient temperature for 45 minutes
7. customRemove cold bath
8. temperatureto warm for 15 minutes
9. temperaturethen cool back to −78° C
10. customCannulate into a −78° C.
11. customover 5-10 minutes
12. customthen remove cold bath
13. temperatureto warm for 15 minutes (to approximately −45° C.)
14. temperatureCool to −78° C.
15. additionadd the dried 2,4,6-tris(1-methylethyl)-benzenesulfonyl azide solution via cannula over 5-10 minutes
16. customRemove bath
17. temperatureto warm to −5 to 0° C. over 1 hour
18. temperatureCool in ice/water bath
19. temperatureAllow to warm to ambient temperature over 65 minutes
20. customquench with saturated sodium bicarbonate solution (14
21. additionDilute
22. customreaction with ethyl acetate (600 mL) and water (2 L)
23. customseparate layers
24. extractionback extract from aqueous with ethyl acetate (2×400 mL)
25. washWash
26. dry with materialdry over sodium sulfate
27. concentrationconcentrate
28. customPurify the residue by flash chromatography
29. washeluting with ethyl acetate:hexane (0:100 to 100:0)